Efficacy and Safety of MEDI6570 in Patients with a History of Myocardial Infarction - GOLDILOX

Study identifier:D4920C00002

ClinicalTrials.gov identifier:NCT04610892

EudraCT identifier:2020-000840-75

CTIS identifier:N/A

Study Complete

Official Title

A Phase IIB, Randomized, Double blinded, Placebo controlled, Parallel group Study to Evaluate the Efficacy and Safety of MEDI6570 in Participants with a Prior Myocardial Infarction and Persistent Inflammation

Medical condition

Coronary Heart Disease (CHD)

Phase

Phase 2

Healthy volunteers

Study drug

Sex

All

Actual Enrollment

423

Study type

Interventional

Age

21 Years - n/a

Date

Study Start Date: 04 Nov 2020

Primary Completion Date: 08 Nov 2023

Study Completion Date: 08 Nov 2023

Study design

Allocation: Randomized
Endpoint Classification: -
Intervention Model: Parallel Assignment
Masking: -
Primary Purpose: Treatment

Verification:

Verified 01 Jan 2025 by AstraZeneca

Collaborators

Thrombolysis in Myocardial Infarction (TIMI) Study Group

Inclusion and exclusion criteria

Inclusion Criteria

1 Participant must provide informed consent before any study specific activities are performed, must be able and willing to meet all requirements for randomization within 42 days after signing the full ICF, and must adhere to the schedules of activities.
2 Women must be ≥ 40 years of age at the time of signing the ICF. Men must be ≥ 21 years of age at the time of signing the ICF.
3 Participant must:
(a) be 30 to 365 days after presumed type-1 (ie, due to plaque rupture or erosion) MI (either STEMI or NSTEMI) at the time of enrollment.
(b) have persistent inflammation, defined as hs CRP ≥ 1 mg/L, as measured centrally at screening Visit 1.
4 Participant must have body mass index within the range 18 to 40 kg/m2 inclusive.
5 For female participants, the participant must not be pregnant or lactating and must be of non-childbearing potential, confirmed at screening Visit 1 by one of the following:
(a) Postmenopausal, defined as amenorrhea for ≥ 12 months following cessation of all exogenous hormonal treatments, and with luteinizing hormone and follicle stimulating hormone levels in the postmenopausal range.
(b) Documentation of irreversible surgical sterilization by hysterectomy, bilateral oophorectomy, or bilateral salpingectomy. Tubal ligation is not considered as irreversible surgical sterilization.
6 Participant must have an evaluable, pre-randomization CTA with quantifiable, non calcified plaque.

Exclusion Criteria

1 History of any clinically important disease or disorder which, in the opinion of the investigator, may either put the participant at risk because of participation in the study, or influence the results or the participant’s ability to participate in the study.
2 Percutaneous coronary intervention or diagnostic angiogram planned after screening. Eligible participants who have a diagnostic angiogram performed in the absence of undergoing a new PCI may continue screening after the diagnostic angiogram has been performed or may be rescreened.
3 History of or planned coronary artery bypass grafting.
4 Documented episode of post-MI pericarditis in the 3 months before enrollment.
5 Ongoing New York Heart Association Class IV HF.
6 Increased risk of bleeding
(a) Patients with history or presence of any bleeding disorder.
(b) Signs of ongoing bleeding at screening (eg, identified macroscopic bleeding, low hemoglobin presumed to be caused by bleeding) or high risk for major bleeding in accordance with the Investigator’s assessment.
(c) Need for chronic therapeutic anticoagulation therapy anticipated to be required throughout the course of the study (short-term treatment with prophylactic doses of heparin/low molecular weight heparin are allowed).
(d) Known severe liver disease.
7 History or presence of any of the following:
(a) Ongoing infection or febrile illness that in the opinion of the investigator may be the cause of elevated hs-CRP on screening.
(b) Ongoing atrial fibrillation or flutter.
(c) Cancer within 5 years before randomization, with the exception of non melanoma skin cancer.
(d) Alcohol or substance abuse within 6 months before randomization, as judged by the investigator.
(e) Known history of hypersensitivity reactions to other biologics, to human IgG preparations, or to any component of MEDI6570, or ongoing severe allergy as judged by the investigator.
(f) Patients with active positive results on screening for serum hepatitis B surface antigen, hepatitis C antibody, or HIV.
8 Any clinically important abnormalities in clinical chemistry, hematology, coagulation parameters, as judged by the investigator.
9 BP values at screening:
(a) Systolic BP < 90 mmHg or > 180 mmHg.
(b) Diastolic BP > 100 mmHg.
(c) Participants who are excluded based on elevated BP may be rescreened following adequate treatment.
10 Participants with any of the following contraindications to CTA:
(a) eGFR < 50 mL/min/1.73 m2 by the Chronic Kidney Disease Epidemiology Collaboration equation, or end stage renal disease treated with kidney transplant or renal replacement therapy.
(b) Allergy to iodinated contrast.
(c) History of contrast-induced nephropathy.
(d) Contraindication to nitroglycerin.
(e) Rapid heart rate that is uncontrolled by medical therapy.
(f) Inability to hold breath for at least 6 seconds.
11 Receipt of any investigational device or therapy within 6 months or 5 half lives before screening (whichever is longer).
This criterion does NOT apply for inactive, non replicating COVID-19 vaccines approved by Health Authorities or under emergency use authorization.
12 Planned participation in an additional investigational study of an intervention or biologic before the end of the follow-up period. Participation in observational studies or studies without investigational drugs or devices is allowed.
13 Participants who are legally institutionalized.
14 An employee or close relative of an employee of the sponsor, the CRO, or the study site, regardless of the employee or close relative’s role.

Location

Research Site

Madrid, Spain, 28046

Location

Research Site

Budapest, Hungary, 1134

Location

Research Site

Northridge, CA, United States, 91325

Location

Research Site

Mobile, AL, United States, 36608

Location

Research Site

Columbia, MO, United States, 65212

Location

Research Site

Kitakyushu-shi, Japan, 802-8555

Location

Research Site

Beverly Hills, CA, United States, 90211

Location

Research Site

Torrance, CA, United States, 90502

Arms	Assigned Interventions
Experimental: MEDI6570 Low dose Monthly Subcutaneous administration.	Biological/Vaccine: MEDI6570 MEDI6570 Other Name: None
Experimental: MEDI6570 Medium dose Monthly Subcutaneous administration.	Biological/Vaccine: MEDI6570 MEDI6570 Other Name: None
Experimental: MEDI6570 High dose Monthly Subcutaneous administration.	Biological/Vaccine: MEDI6570 MEDI6570 Other Name: None
Placebo Comparator: Placebo Low dose Monthly Subcutaneous administration.	Biological/Vaccine: Placebo Buffer Other Name: None
Placebo Comparator: Placebo Medium dose Monthly Subcutaneous administration	Biological/Vaccine: Placebo Buffer Other Name: None
Placebo Comparator: Placebo High dose Monthly Subcutaneous administration	Biological/Vaccine: Placebo Buffer Other Name: None

Participant Flow

Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
No text entered.

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
No text entered.

Reporting Groups

	Description
MEDI6570 50 mg	Participants received MEDI6570 50 mg every 4 weeks for 32 weeks
MEDI6570 150 mg	Participants received MEDI6570 150 mg every 4 weeks for 32 weeks
MEDI6570 250 mg/400 mg	Participants received MEDI6570 250 mg/400 mg every 4 weeks for 32 weeks.
MEDI6570 400 mg	Participants received MEDI6570 400 mg every 4 weeks for 32 weeks
Placebo	Participants received Placebo matched to MEDI6570 every 4 weeks for 32 weeks

Participant Flow: Overall Study

	MEDI6570 50 mg	MEDI6570 150 mg	MEDI6570 250 mg/400 mg	MEDI6570 400 mg	Placebo
STARTED	40	129	8^[2]	118	128
COMPLETED	35	126	8	110	117
NOT COMPLETED	5	3	0	8	11
Adverse Event	1	0	0	1	3
Death	0	1	0	1	0
Withdrawal by Subject	3	2	0	6	6
Subjects who did not receive treatment	1	0	0	0	2

[2]	MEDI6570 250 mg/400 mg : subjects initially randomized to 250 mg that switched dose to 400 mg during the trial.

Baseline Characteristics

Analysis Population Description -- Explanation of how the number of participants for analysis was determined.

8 subjects initially randomized to the 250 mg group switched dose to 400 mg following CSP amendment 1 and were analysed according to the 400 mg group.

Reporting Groups

	Description
MEDI6570 50 mg	Participants received MEDI6570 50 mg every 4 weeks for 32 weeks
MEDI6570 150 mg	Participants received MEDI6570 150 mg every 4 weeks for 32 weeks
MEDI6570 400 mg	Participants received MEDI6570 400 mg every 4 weeks for 32 weeks
Placebo	Participants received Placebo matched to MEDI6570 every 4 weeks for 32 weeks

Baseline Measures

	MEDI6570 50 mg	MEDI6570 150 mg	MEDI6570 400 mg	Placebo	Total
Number of Participants [units: Participants]	40	129	126	128	423
Ethnicity (NIH/OMB) [units: Participants]
Hispanic or Latino	5	5	2	7	19
Not Hispanic or Latino	35	124	124	121	404
Unknown	0	0	0	0	0
Sex: Female, Male [units: Participants]
Female	12	19	23	21	75
Male	28	110	103	107	348
Race (NIH/OMB) [units: Participants]
AMERICAN INDIAN OR ALASKA NATIVE	0	0	0	1	1
ASIAN	7	10	8	9	34
BLACK OR AFRICAN AMERICAN	0	1	0	0	1
NATIVE HAWAIIAN OR OTHER PACIFIC ISLANDER	0	1	0	0	1
OTHER	0	1	0	0	1
WHITE	33	116	118	118	385
Region of Enrollment [units: Participants]
Australia	0	6	6	3	15
Canada	0	3	1	0	4
Czech Republic	2	17	17	18	54
Hungary	9	11	12	23	55
Italy	0	14	21	19	54
Japan	7	9	8	8	32
Netherlands	1	18	11	11	41
Poland	2	14	14	10	40
Spain	13	20	18	18	69
United Kingdom	0	5	5	1	11
United States of America	6	12	13	17	48
Race/Ethnicity, Customized [units: Participants]
Caucasian	33	116	118	118	385
Non-caucasian	7	13	8	10	38
Missing	0	0	0	0	0
Age Continuous [units: Years] Mean ± Standard Deviation	60.1 ± 8.3	59.9 ± 9.2	59.4 ± 9.6	60.4 ± 9.5	59.9 ± 9.3

Outcome Measures

1. Primary Outcome Measure: Change from baseline to Day 253 in non-calcified plaque volume in the most diseased coronary segment (NCPVMD), as measured by Computed Tomography Angiography (CTA) imaging [ Time Frame: From baseline to Day 253 ]

Measure Type	Primary
Measure Name	Change from baseline to Day 253 in non-calcified plaque volume in the most diseased coronary segment (NCPVMD), as measured by Computed Tomography Angiography (CTA) imaging
Measure Description	To evaluate the effect of MEDI6570 on non-calcified coronary atherosclerotic plaques compared with placebo. The primary endpoint of change in NCPVMD from baseline to Day 253 was assessed based on the CTA Analysis Populations.
Time Frame	From baseline to Day 253
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Participants within the Intention To Treat (ITT) Population who had interpretable CTA scans at baseline and at Day 253. Participants were analyzed according to their randomized treatment group. Subjects initially randomized to the 250 mg group switched dose to 400 mg following clinical study protocol (CSP) amendment 1 and were analysed according to the 400 mg group.

Reporting Groups

	Description
MEDI6570 50 mg	Participants received MEDI6570 50 mg every 4 weeks for 32 weeks
MEDI6570 150 mg	Participants received MEDI6570 150 mg every 4 weeks for 32 weeks
MEDI6570 400 mg	Participants received MEDI6570 400 mg every 4 weeks for 32 weeks
MEDI6570 150 mg or 400 mg	Participants received MEDI6570 150 mg or 400 mg every 4 weeks for 32 weeks
Placebo	Participants received Placebo matched to MEDI6570 every 4 weeks for 32 weeks

Measured Values

	MEDI6570 50 mg	MEDI6570 150 mg	MEDI6570 400 mg	MEDI6570 150 mg or 400 mg	Placebo
Number of Participants Analyzed [units:participants]	35	127	118	245	117
Change from baseline to Day 253 in non-calcified plaque volume in the most diseased coronary segment (NCPVMD), as measured by Computed Tomography Angiography (CTA) imaging [units: mm^3] Least Squares Mean (Standard Error)	-15.3220 (4.9219)	-4.5509 (3.1654)	-6.3658 (3.2559)	-5.4220 (2.6622)	-6.9424 (3.2729)

Statistical Analysis 1 for Change from baseline to Day 253 in non-calcified plaque volume in the most diseased coronary segment (NCPVMD), as measured by Computed Tomography Angiography (CTA) imaging

Groups^[1]	MEDI6570 50 mg, Placebo
Method^[3]	ANCOVA
P-Value^[4]	0.065
Other^[5]	-8.3797
90% Confidence Interval	( -17.4980 to 0.7387 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	The treatment as a fixed effects and the baseline value and the geographic region and statin therapy intensity at screening as covariates.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	One-sided p-value
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 2 for Change from baseline to Day 253 in non-calcified plaque volume in the most diseased coronary segment (NCPVMD), as measured by Computed Tomography Angiography (CTA) imaging

Groups^[1]	MEDI6570 150 mg, Placebo
Method^[3]	ANCOVA
P-Value^[4]	0.747
Other^[5]	2.3915
90% Confidence Interval	( -3.5338 to 8.3167 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	The treatment as a fixed effects and the baseline value and the geographic region and statin therapy intensity at screening as covariates.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	One-sided p-value
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 3 for Change from baseline to Day 253 in non-calcified plaque volume in the most diseased coronary segment (NCPVMD), as measured by Computed Tomography Angiography (CTA) imaging

Groups^[1]	MEDI6570 400 mg, Placebo
Method^[3]	ANCOVA
P-Value^[4]	0.563
Other^[5]	0.5766
90% Confidence Interval	( -5.4389 to 6.5921 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	The treatment as a fixed effects and the baseline value and the geographic region and statin therapy intensity at screening as covariates.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	One-sided p-value
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 4 for Change from baseline to Day 253 in non-calcified plaque volume in the most diseased coronary segment (NCPVMD), as measured by Computed Tomography Angiography (CTA) imaging

Groups^[1]	MEDI6570 150 mg or 400 mg, Placebo
Method^[3]	ANCOVA
P-Value^[4]	0.685
Other^[5]	1.5204
90% Confidence Interval	( -3.6657 to 6.7064 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	The treatment as a fixed effects and the baseline value and the geographic region and statin therapy intensity at screening as covariates.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	One-sided p-value
[5]	Other relevant estimation information:
	No text entered.

2. Secondary Outcome Measure: Change from baseline to Day 253 in N Terminal Prohormone Brain Natriuretic Peptide (NT-proBNP) [ Time Frame: From baseline to Day 253 ]

Measure Type	Secondary
Measure Name	Change from baseline to Day 253 in N Terminal Prohormone Brain Natriuretic Peptide (NT-proBNP)
Measure Description	To evaluate the effect of MEDI6570 on a surrogate biomarker of Heart Failure (HF) compared with placebo
Time Frame	From baseline to Day 253
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Randomized subjects who received any study treatment will be included in the As-treated Population. Subjects will be analysed according to the actual treatment they received, regardless of their randomized treatment group. Subjects treated within 250 mg group that received at least one 400 mg dose during the study will be analysed according to the 400mg group.

Reporting Groups

	Description
MEDI6570 50 mg	Participants received MEDI6570 50 mg every 4 weeks for 32 weeks
MEDI6570 150 mg	Participants received MEDI6570 150 mg every 4 weeks for 32 weeks
MEDI6570 400 mg	Participants received MEDI6570 400 mg every 4 weeks for 32 weeks
MEDI6570 150 mg or 400 mg	Participants received MEDI6570 150 mg or 400 mg every 4 weeks for 32 weeks
Placebo	Participants received Placebo matched to MEDI6570 every 4 weeks for 32 weeks

Measured Values

	MEDI6570 50 mg	MEDI6570 150 mg	MEDI6570 400 mg	MEDI6570 150 mg or 400 mg	Placebo
Number of Participants Analyzed [units:participants]	35	125	123	248	118
Change from baseline to Day 253 in N Terminal Prohormone Brain Natriuretic Peptide (NT-proBNP) [units: pg/mL] Geometric Least Squares Mean (Geometric Coefficient of Variation)	0.8226 (9.4%)	0.7787 (5.5%)	0.7368 (5.6%)	0.7575 (4.4%)	0.7370 (5.6%)

Statistical Analysis 1 for Change from baseline to Day 253 in N Terminal Prohormone Brain Natriuretic Peptide (NT-proBNP)

Groups^[1]	MEDI6570 50 mg, Placebo
Method^[3]	Other [Mixed model with repeated measurements]
P-Value^[4]	0.854
Other^[5]	1.12
90% Confidence Interval	( 0.94 to 1.33 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	The model was adjusted for the baseline value and the stratification factors (geographic region and statin therapy intensity at screening).
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	One sided p-value
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 2 for Change from baseline to Day 253 in N Terminal Prohormone Brain Natriuretic Peptide (NT-proBNP)

Groups^[1]	MEDI6570 150 mg, Placebo
Method^[3]	Other [Mixed model with repeated measurements]
P-Value^[4]	0.790
Other^[5]	1.06
90% Confidence Interval	( 0.94 to 1.18 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	The model was adjusted for the baseline value and the stratification factors (geographic region and statin therapy intensity at screening).
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	One sided p-value
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 3 for Change from baseline to Day 253 in N Terminal Prohormone Brain Natriuretic Peptide (NT-proBNP)

Groups^[1]	MEDI6570 400 mg, Placebo
Method^[3]	Other [Mixed model with repeated measurements]
P-Value^[4]	0.498
Other^[5]	1.00
90% Confidence Interval	( 0.89 to 1.12 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	The model was adjusted for the baseline value and the stratification factors (geographic region and statin therapy intensity at screening).
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	One sided p-value
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 4 for Change from baseline to Day 253 in N Terminal Prohormone Brain Natriuretic Peptide (NT-proBNP)

Groups^[1]	MEDI6570 150 mg or 400 mg, Placebo
Method^[3]	Other [Mixed model with repeated measurements]
P-Value^[4]	0.678
Other^[5]	1.03
90% Confidence Interval	( 0.93 to 1.13 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	The model was adjusted for the baseline value and the stratification factors (geographic region and statin therapy intensity at screening).
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	One sided p-value
[5]	Other relevant estimation information:
	No text entered.

3. Secondary Outcome Measure: Change from baseline to Day 253 in Left Ventricular Ejection Fraction (LVEF) [ Time Frame: From baseline to Day 253 ]

Measure Type	Secondary
Measure Name	Change from baseline to Day 253 in Left Ventricular Ejection Fraction (LVEF)
Measure Description	To evaluate the effect of MEDI6570 on left ventricular systolic function compared with placebo
Time Frame	From baseline to Day 253
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Subjects within the ITT population who have interpretable echocardiograms in the baseline and follow-up periods will be included in the Echocardiogram Analysis Population. Subjects will be analysed according to their randomized treatment group. subjects initially randomized to the 250 mg group switched dose to 400 mg following CSP amendment 1 and were analysed according to the 400 mg group

Reporting Groups

	Description
MEDI6570 50 mg	Participants received MEDI6570 50 mg every 4 weeks for 32 weeks
MEDI6570 150 mg	Participants received MEDI6570 150 mg every 4 weeks for 32 weeks
MEDI6570 400 mg	Participants received MEDI6570 400 mg every 4 weeks for 32 weeks
MEDI6570 150 mg or 400 mg	Participants received MEDI6570 150 mg or 400 mg every 4 weeks for 32 weeks
Placebo	Participants received Placebo matched to MEDI6570 every 4 weeks for 32 weeks

Measured Values

	MEDI6570 50 mg	MEDI6570 150 mg	MEDI6570 400 mg	MEDI6570 150 mg or 400 mg	Placebo
Number of Participants Analyzed [units:participants]	31	115	112	227	103
Change from baseline to Day 253 in Left Ventricular Ejection Fraction (LVEF) [units: Percentage of LVEF] Least Squares Mean (Standard Error)	-0.91 (0.55)	0.32 (0.34)	0.11 (0.35)	0.22 (0.28)	0.53 (0.35)

Statistical Analysis 1 for Change from baseline to Day 253 in Left Ventricular Ejection Fraction (LVEF)

Groups^[1]	MEDI6570 50 mg, Placebo
Method^[3]	ANCOVA
P-Value^[4]	0.990
Other^[5]	-1.44
90% Confidence Interval	( -2.44 to -0.43 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	The model was adjusted for the baseline value and stratification factors (geographic region and statin therapy intensity at screening).
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	One sided p-value
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 2 for Change from baseline to Day 253 in Left Ventricular Ejection Fraction (LVEF)

Groups^[1]	MEDI6570 150 mg, Placebo
Method^[3]	ANCOVA
P-Value^[4]	0.697
Other^[5]	-0.21
90% Confidence Interval	( -0.87 to 0.45 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	The model was adjusted for the baseline value and stratification factors (geographic region and statin therapy intensity at screening).
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	One sided p-value
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 3 for Change from baseline to Day 253 in Left Ventricular Ejection Fraction (LVEF)

Groups^[1]	MEDI6570 400 mg, Placebo
Method^[3]	ANCOVA
P-Value^[4]	0.849
Other^[5]	-0.42
90% Confidence Interval	( -1.08 to 0.25 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	The model was adjusted for the baseline value and stratification factors (geographic region and statin therapy intensity at screening).
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	One sided p-value
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 4 for Change from baseline to Day 253 in Left Ventricular Ejection Fraction (LVEF)

Groups^[1]	MEDI6570 150 mg or 400 mg, Placebo
Method^[3]	ANCOVA
P-Value^[4]	0.811
Other^[5]	-0.31
90% Confidence Interval	( -0.89 to 0.27 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	The model was adjusted for the baseline value and stratification factors (geographic region and statin therapy intensity at screening).
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	One sided p-value
[5]	Other relevant estimation information:
	No text entered.

4. Secondary Outcome Measure: Left ventricular ejection fraction (LVEF) change from baseline to Day 253 among subjects with reduced ejection fraction (< 50%) [ Time Frame: From baseline to Day 253 ]

Measure Type	Secondary
Measure Name	Left ventricular ejection fraction (LVEF) change from baseline to Day 253 among subjects with reduced ejection fraction (< 50%)
Measure Description	To evaluate the effect of MEDI6570 on left ventricular systolic function among participants with reduced ejection fraction (defined as <50%) compared with placebo
Time Frame	From baseline to Day 253
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Subjects within the ITT population who have interpretable echocardiograms in the baseline and follow-up periods will be included in the Echocardiogram Analysis Population. Subjects will be analysed according to their randomized treatment group. Subjects initially randomized to the 250 mg group switched dose to 400 mg following CSP amendment 1 and were analysed according to the 400 mg group.

Reporting Groups

	Description
MEDI6570 50 mg	Participants received MEDI6570 50 mg every 4 weeks for 32 weeks
MEDI6570 150 mg	Participants received MEDI6570 150 mg every 4 weeks for 32 weeks
MEDI6570 400 mg	Participants received MEDI6570 400 mg every 4 weeks for 32 weeks
MEDI6570 150 mg or 400 mg	Participants received MEDI6570 150 mg or 400 mg every 4 weeks for 32 weeks
Placebo	Participants received Placebo matched to MEDI6570 every 4 weeks for 32 weeks

Measured Values

	MEDI6570 50 mg	MEDI6570 150 mg	MEDI6570 400 mg	MEDI6570 150 mg or 400 mg	Placebo
Number of Participants Analyzed [units:participants]	7	13	20	33	14
Left ventricular ejection fraction (LVEF) change from baseline to Day 253 among subjects with reduced ejection fraction (< 50%) [units: Percentage of LVEF] Least Squares Mean (Standard Error)	-1.08 (1.52)	1.32 (1.13)	2.09 (1.00)	1.79 (0.82)	2.41 (1.04)

Statistical Analysis 1 for Left ventricular ejection fraction (LVEF) change from baseline to Day 253 among subjects with reduced ejection fraction (< 50%)

Groups^[1]	MEDI6570 50 mg, Placebo
Method^[3]	ANCOVA
P-Value^[4]	0.972
Other^[5]	-3.50
90% Confidence Interval	( -6.49 to -0.50 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	The model was adjusted for the baseline value and stratification factors (geographic region and statin therapy intensity at screening).
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	One sided p-value
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 2 for Left ventricular ejection fraction (LVEF) change from baseline to Day 253 among subjects with reduced ejection fraction (< 50%)

Groups^[1]	MEDI6570 150 mg, Placebo
Method^[3]	ANCOVA
P-Value^[4]	0.777
Other^[5]	-1.10
90% Confidence Interval	( -3.49 to 1.30 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	The model was adjusted for the baseline value and stratification factors (geographic region and statin therapy intensity at screening).
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	One sided p-value
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 3 for Left ventricular ejection fraction (LVEF) change from baseline to Day 253 among subjects with reduced ejection fraction (< 50%)

Groups^[1]	MEDI6570 400 mg, Placebo
Method^[3]	ANCOVA
P-Value^[4]	0.596
Other^[5]	-0.32
90% Confidence Interval	( -2.54 to 1.89 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	The model was adjusted for the baseline value and stratification factors (geographic region and statin therapy intensity at screening).
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	One sided p-value
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 4 for Left ventricular ejection fraction (LVEF) change from baseline to Day 253 among subjects with reduced ejection fraction (< 50%)

Groups^[1]	MEDI6570 150 mg or 400 mg, Placebo
Method^[3]	ANCOVA
P-Value^[4]	0.698
Other^[5]	-0.63
90% Confidence Interval	( -2.64 to 1.38 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	The model was adjusted for the baseline value and stratification factors (geographic region and statin therapy intensity at screening).
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	One sided p-value
[5]	Other relevant estimation information:
	No text entered.

5. Secondary Outcome Measure: Change from baseline to Day 253 in Global Longitudinal Strain (GLS) [ Time Frame: From baseline to Day 253 ]

Measure Type	Secondary
Measure Name	Change from baseline to Day 253 in Global Longitudinal Strain (GLS)
Measure Description	To evaluate the effect of MEDI6570 on left ventricular systolic function compared with placebo
Time Frame	From baseline to Day 253
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Subjects within the ITT population who have interpretable echocardiograms in the baseline and follow-up periods will be included in the Echocardiogram Analysis Population. Subjects will be analysed according to their randomized treatment group. Subjects initially randomized to the 250 mg group switched dose to 400 mg following CSP amendment 1 and were analysed according to the 400 mg group.

Reporting Groups

	Description
MEDI6570 50 mg	Participants received MEDI6570 50 mg every 4 weeks for 32 weeks
MEDI6570 150 mg	Participants received MEDI6570 150 mg every 4 weeks for 32 weeks
MEDI6570 400 mg	Participants received MEDI6570 400 mg every 4 weeks for 32 weeks
MEDI6570 150 mg or 400 mg	Participants received MEDI6570 150 mg or 400 mg every 4 weeks for 32 weeks
Placebo	Participants received Placebo matched to MEDI6570 every 4 weeks for 32 weeks

Measured Values

	MEDI6570 50 mg	MEDI6570 150 mg	MEDI6570 400 mg	MEDI6570 150 mg or 400 mg	Placebo
Number of Participants Analyzed [units:participants]	29	105	109	214	100
Change from baseline to Day 253 in Global Longitudinal Strain (GLS) [units: Percentage of GLS] Least Squares Mean (Standard Error)	-1.20 (0.56)	-0.70 (0.35)	-0.77 (0.35)	-0.74 (0.29)	0.09 (0.35)

Statistical Analysis 1 for Change from baseline to Day 253 in Global Longitudinal Strain (GLS)

Groups^[1]	MEDI6570 50 mg, Placebo
Method^[3]	ANCOVA
P-Value^[4]	0.981
Other^[5]	-1.29
90% Confidence Interval	( -2.32 to -0.27 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	The model was adjusted for the baseline value and stratification factors (geographic region and statin therapy intensity at screening).
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	One sided p-value
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 2 for Change from baseline to Day 253 in Global Longitudinal Strain (GLS)

Groups^[1]	MEDI6570 150 mg, Placebo
Method^[3]	ANCOVA
P-Value^[4]	0.974
Other^[5]	-0.80
90% Confidence Interval	( -1.47 to -0.12 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	The model was adjusted for the baseline value and stratification factors (geographic region and statin therapy intensity at screening).
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	One sided p-value
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 3 for Change from baseline to Day 253 in Global Longitudinal Strain (GLS)

Groups^[1]	MEDI6570 400 mg, Placebo
Method^[3]	ANCOVA
P-Value^[4]	0.983
Other^[5]	-0.86
90% Confidence Interval	( -1.53 to -0.20 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	The model was adjusted for the baseline value and stratification factors (geographic region and statin therapy intensity at screening).
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	One sided p-value
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 4 for Change from baseline to Day 253 in Global Longitudinal Strain (GLS)

Groups^[1]	MEDI6570 150 mg or 400 mg, Placebo
Method^[3]	ANCOVA
P-Value^[4]	0.990
Other^[5]	-0.83
90% Confidence Interval	( -1.42 to -0.25 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	The model was adjusted for the baseline value and stratification factors (geographic region and statin therapy intensity at screening).
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	One sided p-value
[5]	Other relevant estimation information:
	No text entered.

6. Secondary Outcome Measure: Global longitudinal strain (GLS) change from baseline to Day 253 among subjects with reduced ejection fraction (< 50%) [ Time Frame: From baseline to Day 253 ]

Measure Type	Secondary
Measure Name	Global longitudinal strain (GLS) change from baseline to Day 253 among subjects with reduced ejection fraction (< 50%)
Measure Description	To evaluate the effect of MEDI6570 on left ventricular systolic function among participants with reduced ejection fraction (defined as <50%) compared with placebo
Time Frame	From baseline to Day 253
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Subjects within the ITT population who have interpretable echocardiograms in the baseline and follow-up periods will be included in the Echocardiogram Analysis Population. Subjects will be analysed according to their randomized treatment group. Subjects initially randomized to the 250 mg group switched dose to 400 mg following CSP amendment 1 and were analysed according to the 400 mg group.

Reporting Groups

	Description
MEDI6570 50 mg	Participants received MEDI6570 50 mg every 4 weeks for 32 weeks
MEDI6570 150 mg	Participants received MEDI6570 150 mg every 4 weeks for 32 weeks
MEDI6570 400 mg	Participants received MEDI6570 400 mg every 4 weeks for 32 weeks
MEDI6570 150 mg or 400 mg	Participants received MEDI6570 150 mg or 400 mg every 4 weeks for 32 weeks
Placebo	Participants received Placebo matched to MEDI6570 every 4 weeks for 32 weeks

Measured Values

	MEDI6570 50 mg	MEDI6570 150 mg	MEDI6570 400 mg	MEDI6570 150 mg or 400 mg	Placebo
Number of Participants Analyzed [units:participants]	6	12	20	32	15
Global longitudinal strain (GLS) change from baseline to Day 253 among subjects with reduced ejection fraction (< 50%) [units: Percentage of GLS] Least Squares Mean (Standard Error)	-0.39 (1.03)	-1.16 (0.78)	0.41 (0.64)	-0.19 (0.55)	1.76 (0.66)

Statistical Analysis 1 for Global longitudinal strain (GLS) change from baseline to Day 253 among subjects with reduced ejection fraction (< 50%)

Groups^[1]	MEDI6570 50 mg, Placebo
Method^[3]	ANCOVA
P-Value^[4]	0.959
Other^[5]	-2.14
90% Confidence Interval	( -4.16 to -0.12 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	The model was adjusted for the baseline value and stratification factors (geographic region and statin therapy intensity at screening).
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	One sided p-value
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 2 for Global longitudinal strain (GLS) change from baseline to Day 253 among subjects with reduced ejection fraction (< 50%)

Groups^[1]	MEDI6570 150 mg, Placebo
Method^[3]	ANCOVA
P-Value^[4]	0.998
Other^[5]	-2.92
90% Confidence Interval	( -4.53 to -1.31 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	The model was adjusted for the baseline value and stratification factors (geographic region and statin therapy intensity at screening).
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	One sided p-value
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 3 for Global longitudinal strain (GLS) change from baseline to Day 253 among subjects with reduced ejection fraction (< 50%)

Groups^[1]	MEDI6570 400 mg, Placebo
Method^[3]	ANCOVA
P-Value^[4]	0.939
Other^[5]	-1.35
90% Confidence Interval	( -2.79 to 0.09 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	The model was adjusted for the baseline value and stratification factors (geographic region and statin therapy intensity at screening).
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	One sided p-value
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 4 for Global longitudinal strain (GLS) change from baseline to Day 253 among subjects with reduced ejection fraction (< 50%)

Groups^[1]	MEDI6570 150 mg or 400 mg, Placebo
Method^[3]	ANCOVA
P-Value^[4]	0.991
Other^[5]	-1.94
90% Confidence Interval	( -3.27 to -0.62 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	The model was adjusted for the baseline value and stratification factors (geographic region and statin therapy intensity at screening).
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	One sided p-value
[5]	Other relevant estimation information:
	No text entered.

7. Secondary Outcome Measure: Change from baseline to Day 253 in Global non-calcified plaque volume (NCPV) [ Time Frame: From baseline to Day 253 ]

Measure Type	Secondary
Measure Name	Change from baseline to Day 253 in Global non-calcified plaque volume (NCPV)
Measure Description	To evaluate the effect of MEDI6570 on other measures of non-calcified coronary atherosclerotic plaque compared with placebo
Time Frame	From baseline to Day 253
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.

Participants within the ITT Population who had interpretable b CTA scans at baseline and at Day 253 or at Day 122 were included. (Note that separate analyses were conducted for Day 253 and Day 122). Participants were analyzed according to their randomized treatment group. Subjects initially randomized to the 250 mg group switched dose to 400 mg following CSP amendment 1 and were analysed according to the 400 mg group.

Reporting Groups

	Description
MEDI6570 50 mg	Participants received MEDI6570 50 mg every 4 weeks for 32 weeks
MEDI6570 150 mg	Participants received MEDI6570 150 mg every 4 weeks for 32 weeks
MEDI6570 400 mg	Participants received MEDI6570 400 mg every 4 weeks for 32 weeks
MEDI6570 150 mg or 400 mg	Participants received MEDI6570 150 mg or 400 mg every 4 weeks for 32 weeks
Placebo	Participants received Placebo matched to MEDI6570 every 4 weeks for 32 weeks

Measured Values

	MEDI6570 50 mg	MEDI6570 150 mg	MEDI6570 400 mg	MEDI6570 150 mg or 400 mg	Placebo
Number of Participants Analyzed [units:participants]	34	125	116	241	117
Change from baseline to Day 253 in Global non-calcified plaque volume (NCPV) [units: mm^3] Least Squares Mean (Standard Error)	-26.4453 (10.0524)	-10.9010 (6.4671)	-10.4850 (6.6607)	-10.7013 (5.4415)	-10.3083 (6.7052)

Statistical Analysis 1 for Change from baseline to Day 253 in Global non-calcified plaque volume (NCPV)

Groups^[1]	MEDI6570 50 mg, Placebo
Method^[3]	ANCOVA
P-Value^[4]	0.077
Other^[5]	-16.1370
90% Confidence Interval	( -34.7829 to 2.5089 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	The model was adjusted for the baseline value and stratification factors (geographic region and statin therapy intensity at screening).
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	One sided p-value
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 2 for Change from baseline to Day 253 in Global non-calcified plaque volume (NCPV)

Groups^[1]	MEDI6570 150 mg, Placebo
Method^[3]	ANCOVA
P-Value^[4]	0.468
Other^[5]	-0.5927
90% Confidence Interval	( -12.7267 to 11.5413 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	The model was adjusted for the baseline value and stratification factors (geographic region and statin therapy intensity at screening).
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	One sided p-value
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 3 for Change from baseline to Day 253 in Global non-calcified plaque volume (NCPV)

Groups^[1]	MEDI6570 400 mg, Placebo
Method^[3]	ANCOVA
P-Value^[4]	0.491
Other^[5]	-0.1767
90% Confidence Interval	( -12.4678 to 12.1144 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	The model was adjusted for the baseline value and stratification factors (geographic region and statin therapy intensity at screening).
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	One sided p-value
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 4 for Change from baseline to Day 253 in Global non-calcified plaque volume (NCPV)

Groups^[1]	MEDI6570 150 mg or 400 mg, Placebo
Method^[3]	ANCOVA
P-Value^[4]	0.476
Other^[5]	-0.3930
90% Confidence Interval	( -11.0022 to 10.2162 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	The model was adjusted for the baseline value and stratification factors (geographic region and statin therapy intensity at screening).
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	One sided p-value
[5]	Other relevant estimation information:
	No text entered.

8. Secondary Outcome Measure: Change from baseline to Day 253 in Low attenuation plaque volume (LAPV) [ Time Frame: From baseline to Day 253 ]

Measure Type	Secondary
Measure Name	Change from baseline to Day 253 in Low attenuation plaque volume (LAPV)
Measure Description	To evaluate the effect of MEDI6570 on other measures of non-calcified coronary atherosclerotic plaque compared with placebo
Time Frame	From baseline to Day 253
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Participants within the ITT Population who had interpretable CTA scans at baseline and at Day 253. Participants were analyzed according to their randomized treatment group. Subjects initially randomized to the 250 mg group switched dose to 400 mg following CSP amendment 1 and were analysed according to the 400 mg group.

Reporting Groups

	Description
MEDI6570 50 mg	Participants received MEDI6570 50 mg every 4 weeks for 32 weeks
MEDI6570 150 mg	Participants received MEDI6570 150 mg every 4 weeks for 32 weeks
MEDI6570 400 mg	Participants received MEDI6570 400 mg every 4 weeks for 32 weeks
MEDI6570 150 mg or 400 mg	Participants received MEDI6570 150 mg or 400 mg every 4 weeks for 32 weeks
Placebo	Participants received Placebo matched to MEDI6570 every 4 weeks for 32 weeks

Measured Values

	MEDI6570 50 mg	MEDI6570 150 mg	MEDI6570 400 mg	MEDI6570 150 mg or 400 mg	Placebo
Number of Participants Analyzed [units:participants]	34	125	116	241	117
Change from baseline to Day 253 in Low attenuation plaque volume (LAPV) [units: mm3] Least Squares Mean (Standard Error)	-7.9167 (3.5226)	-4.8101 (2.2690)	-4.2748 (2.3363)	-4.5532 (1.9099)	-3.5733 (2.3481)

Statistical Analysis 1 for Change from baseline to Day 253 in Low attenuation plaque volume (LAPV)

Groups^[1]	MEDI6570 50 mg, Placebo
Method^[3]	ANCOVA
P-Value^[4]	0.136
Other^[5]	-4.3435
90% Confidence Interval	( -10.8637 to 2.1768 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	The model was adjusted for the baseline value and stratification factors (geographic region and statin therapy intensity at screening).
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	One sided p-value
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 2 for Change from baseline to Day 253 in Low attenuation plaque volume (LAPV)

Groups^[1]	MEDI6570 150 mg, Placebo
Method^[3]	ANCOVA
P-Value^[4]	0.316
Other^[5]	-1.2369
90% Confidence Interval	( -5.4796 to 3.0059 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	The model was adjusted for the baseline value and stratification factors (geographic region and statin therapy intensity at screening).
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	One sided p-value
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 3 for Change from baseline to Day 253 in Low attenuation plaque volume (LAPV)

Groups^[1]	MEDI6570 400 mg, Placebo
Method^[3]	ANCOVA
P-Value^[4]	0.394
Other^[5]	-0.7015
90% Confidence Interval	( -5.0096 to 3.6065 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	The model was adjusted for the baseline value and stratification factors (geographic region and statin therapy intensity at screening).
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	One sided p-value
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 4 for Change from baseline to Day 253 in Low attenuation plaque volume (LAPV)

Groups^[1]	MEDI6570 150 mg or 400 mg, Placebo
Method^[3]	ANCOVA
P-Value^[4]	0.332
Other^[5]	-0.9799
90% Confidence Interval	( -4.6927 to 2.7329 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	The model was adjusted for the baseline value and stratification factors (geographic region and statin therapy intensity at screening).
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	One sided p-value
[5]	Other relevant estimation information:
	No text entered.

9. Secondary Outcome Measure: Summary of ADA (anti-drug antibody) Responses During the Study [ Time Frame: From baseline to Day 325/405. Day 325/405: for participants who completed the study under clinical study protocol (CSP) Amendment 1 & 2, the end of study visits were Day 405 and Day 325 respectively. ]

Measure Type	Secondary
Measure Name	Summary of ADA (anti-drug antibody) Responses During the Study
Measure Description	To evaluate the immunogenicity of MEDI6570
Time Frame	From baseline to Day 325/405. Day 325/405: for participants who completed the study under clinical study protocol (CSP) Amendment 1 & 2, the end of study visits were Day 405 and Day 325 respectively.
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Subjects included in the As-treated Population who have ≥ 1 immunogenicity sample will be included in the Immunogenicity Population. Subjects will be analysed according to the actual treatment they received. Subjects initially randomized to the 250 mg group switched dose to 400 mg following CSP amendment 1 and were analysed according to the 400 mg group.

Reporting Groups

	Description
MEDI6570 50 mg	Participants received MEDI6570 50 mg very 4 weeks for 32 weeks
MEDI6570 150 mg	Participants received MEDI6570 150 mg very 4 weeks for 32 weeks
MEDI6570 400 mg	Participants received MEDI6570 400 mg very 4 weeks for 32 weeks
MEDI6570 Total	Number of participants received MEDI6570 50 mg, MEDI6570 150 mg and 400 mg
Placebo	Participants received Placebo matched to MEDI6570 very 4 weeks for 32 weeks
Total	Overall Total

Measured Values

	MEDI6570 50 mg	MEDI6570 150 mg	MEDI6570 400 mg	MEDI6570 Total	Placebo	Total
Number of Participants Analyzed [units:participants]	39	129	126	294	126	420
Summary of ADA (anti-drug antibody) Responses During the Study [units: Participants]
ADA (anti-drug antibody) prevalence (positive at baseline or post-baseline)	2	10	3	15	1	16
ADA (anti-drug antibody) incidence (TEADA positive)	2	9	2	13	1	14
Treatment-induced ADA (anti-drug antibody) positive	2	9	2	13	1	14
Treatment-boosted ADA (anti-drug antibody) positive	0	1	0	1	0	1
ADA (anti-drug antibody) persistently positive	2	7	1	10	1	11

No statistical analysis provided for Summary of ADA (anti-drug antibody) Responses During the Study

10. Secondary Outcome Measure: Anti-drug antibody Titre summary by visit [ Time Frame: From Baseline to Day 325/405. Day 325/405: for participants who completed the study under CSP Amendment 1 & 2, the end of study visits were Day 405 and Day 325 respectively. ]

Measure Type	Secondary
Measure Name	Anti-drug antibody Titre summary by visit
Measure Description	To evaluate the immunogenicity of MEDI6570
Time Frame	From Baseline to Day 325/405. Day 325/405: for participants who completed the study under CSP Amendment 1 & 2, the end of study visits were Day 405 and Day 325 respectively.
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Subjects included in the As-treated Population who have ≥ 1 immunogenicity sample will be included in the Immunogenicity Population. Subjects will be analysed according to the actual treatment they received. Subjects initially randomized to the 250 mg group switched dose to 400 mg following CSP amendment 1 and were analysed according to the 400 mg group.

Reporting Groups

	Description
MEDI6570 50 mg	Participants received MEDI6570 50 mg every 4 weeks for 32 weeks
MEDI6570 150 mg	Participants received MEDI6570 150 mg every 4 weeks for 32 weeks
MEDI6570 400 mg	Participants received MEDI6570 400 mg every 4 weeks for 32 weeks
MEDI6570 Total	Number of participants received MEDI6570 50 mg, MEDI6570 150 mg and 400 mg
Placebo	Participants received Placebo matched to MEDI6570 every 4 weeks for 32 weeks
Total	Overall Total

Measured Values

	MEDI6570 50 mg	MEDI6570 150 mg	MEDI6570 400 mg	MEDI6570 Total	Placebo	Total
Number of Participants Analyzed [units:participants]	39	129	126	294	126	420
Anti-drug antibody Titre summary by visit [units: Titer units] Median (Full Range)
Baseline		80 (80 to 80)	320 (320 to 320)	200 (80 to 320)		200 (80 to 320)
Day 29		640 (640 to 640)		640 (640 to 640)		640 (640 to 640)
Day 57		80 (80 to 80)		80 (80 to 80)		80 (80 to 80)
Day 113	640 (640 to 640)	640 (640 to 640)		640 (640 to 640)		640 (640 to 640)
Day 169	320 (320 to 320)	1600 (640 to 2560)		640 (320 to 2560)		640.0 (320 to 2560)
Day 253	160 (160 to 160)	1360 (160 to 2560)	80 (80 to 80)	160 (80 to 2560)		160 (80 to 2560)
Day 325/405	120.0 (80 to 160)	320 (80 to 1280)	80 (80 to 80)	160 (80 to 1280)	NA (NA to NA) ^[1]	160 (80 to 1280)

No statistical analysis provided for Anti-drug antibody Titre summary by visit

11. Secondary Outcome Measure: Summary of serum concentrations (ug/mL) of MEDI6570 [ Time Frame: From baseline to Day 325/Day 405 ]

Measure Type	Secondary
Measure Name	Summary of serum concentrations (ug/mL) of MEDI6570
Measure Description	MEDI6570 concentrations as measured in serum during the intervention and follow-up periods
Time Frame	From baseline to Day 325/Day 405
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
All subjects who received ≥ 1 dose of MEDI6570 and have ≥ 1 one post dose evaluable MEDI6570 serum concentration will be included in the PK population. Subjects will be analysed according to the actual treatment they received. The pk data was analysed only for 50 mg, 150mg and 400mg groups.

Reporting Groups

	Description
MEDI6570 50 mg	Participants received MEDI6570 50 mg every 4 weeks for 32 weeks
MEDI6570 150 mg	Participants received MEDI6570 150 mg every 4 weeks for 32 weeks
MEDI6570 400 mg	Participants received MEDI6570 400 mg every 4 weeks for 32 weeks

Measured Values

	MEDI6570 50 mg	MEDI6570 150 mg	MEDI6570 400 mg
Number of Participants Analyzed [units:participants]	38	129	117
Summary of serum concentrations (ug/mL) of MEDI6570 [units: ug/mL] Geometric Mean (Geometric Coefficient of Variation)
Baseline	NA (NA%)^[1]	NA (NA%)^[1]	NA (NA%)^[1]
Day 10	2.3126 (101.5%)	7.0296 (125.9%)	20.4472 (37.2%)
Day 29	0.6154 (170.7%)	3.4641 (103.2%)	9.5328 (115.4%)
Day 57	0.7622 (235.5%)	4.3897 (145.9%)	15.0108 (50.3%)
Day 85	1.1353 (217.3%)	6.4317 (62.0%)	10.8714 (608.2%)
Day 113	1.0084 (176.7%)	5.4403 (120.1%)	15.5611 (77.1%)
Day 122	4.6703 (37.0%)	8.1229 (792.0%)	28.1805 (168.8%)
Day 141	1.4191 (129.5%)	8.0736 (47.2%)	10.4080 (647.5%)
Day 169	0.8016 (171.6%)	5.2865 (163.4%)	15.9449 (145.9%)
Day 197			NA (NA%)^[1]
Day 225	2.2469 (86.3%)	3.6384 (633.4%)
Day 253	0.7253 (288.4%)	5.6832 (136.0%)	14.9944 (173.4%)
Day 325/Day 405	NA (NA%)^[1]	NA (NA%)^[1]	0.5955 (720.6%)

No statistical analysis provided for Summary of serum concentrations (ug/mL) of MEDI6570

12. Secondary Outcome Measure: Number of Participants with Adverse Events in Any Category [ Time Frame: During study follow-up (from day 1 to day 325) ]

Measure Type	Secondary
Measure Name	Number of Participants with Adverse Events in Any Category
Measure Description	To assess the safety and tolerability of MEDI6570 compared with placebo
Time Frame	During study follow-up (from day 1 to day 325)
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Randomized subjects who received any study treatment will be included in the As-treated Population. Subjects will be analysed according to the actual treatment they received, regardless of their randomized treatment group. Subjects treated within 250 mg group that received at least one 400 mg dose during the study will be analysed according to the 400mg group.

Reporting Groups

	Description
MEDI6570 50 mg	Participants received MEDI6570 50 mg every 4 weeks for 32 weeks
MEDI6570 150 mg	Participants received MEDI6570 150 mg every 4 weeks for 32 weeks
MEDI6570 400 mg	Participants received MEDI6570 400 mg every 4 weeks for 32 weeks
MEDI6570 Total	Participants received MEDI6570 50 mg or 150 mg or 400 mg every 4 weeks for 32 weeks
Placebo	Participants received Placebo matched to MEDI6570 every 4 weeks for 32 weeks

Measured Values

	MEDI6570 50 mg	MEDI6570 150 mg	MEDI6570 400 mg	MEDI6570 Total	Placebo
Number of Participants Analyzed [units:participants]	39	129	126	294	126
Number of Participants with Adverse Events in Any Category [units: participants]
Any AEs	26	87	79	192	65
Any AEs with outcome of death	0	1	1	2	0
Any SAE (including events with outcome of death)	4	17	10	31	13
Any AE leading to treatment discontinuation	1	0	2	3	3
Any AE leading to withdrawal from study	0	0	0	0	0

No statistical analysis provided for Number of Participants with Adverse Events in Any Category

13. Secondary Outcome Measure: Number of Participants with Most Common Adverse Events (Frequency > 5%) [ Time Frame: During study follow-up (from day 1 to day 325) ]

Measure Type	Secondary
Measure Name	Number of Participants with Most Common Adverse Events (Frequency > 5%)
Measure Description	To assess the safety and tolerability of MEDI6570 compared with placebo
Time Frame	During study follow-up (from day 1 to day 325)
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Randomized subjects who received any study treatment will be included in the As-treated Population. Subjects will be analysed according to the actual treatment they received, regardless of their randomized treatment group. Subjects treated within 250 mg group that received at least one 400 mg dose during the study will be analysed according to the 400mg group.

Reporting Groups

	Description
MEDI6570 50 mg	Participants received MEDI6570 50 mg every 4 weeks for 32 weeks
MEDI6570 150 mg	Participants received MEDI6570 150 mg every 4 weeks for 32 weeks
MEDI6570 400 mg	Participants received MEDI6570 400 mg every 4 weeks for 32 weeks
MEDI6570 Total	Participants received MEDI6570 50 mg or 150 mg or 400 mg every 4 weeks for 32 weeks
Placebo	Participants received Placebo matched to MEDI6570 every 4 weeks for 32 weeks

Measured Values

	MEDI6570 50 mg	MEDI6570 150 mg	MEDI6570 400 mg	MEDI6570 Total	Placebo
Number of Participants Analyzed [units:participants]	39	129	126	294	126
Number of Participants with Most Common Adverse Events (Frequency > 5%) [units: participants]
Participants with any AE	16	35	38	89	26
COVID-19	3	8	17	28	6
Hypertension	2	4	9	15	9
Non-cardiac chest pain	3	5	6	14	4
Dyspnoea	2	3	4	9	3
Hypotension	2	1	4	7	1
Angina pectoris	2	10	3	15	6
Pyrexia	2	1	3	6	1
Diarrhoea	2	5	2	9	4
Epistaxis	2	1	2	5	1
Influenza	2	4	2	8	1
Nausea	2	1	1	4	1
Pain in extremity	2	1	1	4	1

No statistical analysis provided for Number of Participants with Most Common Adverse Events (Frequency > 5%)

14. Secondary Outcome Measure: Vital signs (change in systolic and diastolic blood pressure from baseline) over time [ Time Frame: From baseline to Day 325/405. Day 325/405: for participants who completed the study under CSP Amendment 1 & 2, the end of study visits were Day 405 and Day 325 respectively. ]

Measure Type	Secondary
Measure Name	Vital signs (change in systolic and diastolic blood pressure from baseline) over time
Measure Description	To assess the safety and tolerability of MEDI6570 compared with placebo
Time Frame	From baseline to Day 325/405. Day 325/405: for participants who completed the study under CSP Amendment 1 & 2, the end of study visits were Day 405 and Day 325 respectively.
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Randomized subjects who received any study treatment will be included in the As-treated Population. Subjects will be analysed according to the actual treatment they received, regardless of their randomized treatment group. Subjects treated within 250 mg group that received at least one 400 mg dose during the study will be analysed according to the 400mg group.

Reporting Groups

	Description
MEDI6570 50 mg	Participants received MEDI6570 50 mg every 4 weeks for 32 weeks
MEDI6570 150 mg	Participants received MEDI6570 150 mg every 4 weeks for 32 weeks
MEDI6570 400 mg	Participants received MEDI6570 400 mg every 4 weeks for 32 weeks
Placebo	Participants received Placebo matched to MEDI6570 every 4 weeks for 32 weeks

Measured Values

	MEDI6570 50 mg	MEDI6570 150 mg	MEDI6570 400 mg	Placebo
Number of Participants Analyzed [units:participants]	39	129	126	126
Vital signs (change in systolic and diastolic blood pressure from baseline) over time [units: mmHg] Mean (Standard Deviation)
Systolic blood pressure Day 10	0.3 (9.9)	0.9 (12.7)	-1.4 (13.0)	0.4 (12.8)
Systolic blood pressure Day 29	-0.7 (10.8)	-1.1 (14.6)	-1.5 (11.9)	-1.3 (12.6)
Systolic blood pressure Day 57	1.4 (11.6)	0.7 (14.1)	-1.6 (12.3)	-0.1 (12.8)
Systolic blood pressure Day 85	0.7 (10.2)	1.5 (13.8)	-1.2 (12.7)	-0.5 (14.9)
Systolic blood pressure Day 113	-0.6 (10.6)	1.3 (15.2)	0.2 (13.7)	0.6 (13.1)
Systolic blood pressure Day 122	1.6 (16.4)	-4.0 (15.5)	-2.0 (13.8)	7.8 (17.1)
Systolic blood pressure Day 141	0.7 (15.0)	-0.2 (14.1)	-0.2 (14.1)	0.8 (13.3)
Systolic blood pressure Day 169	1.2 (13.4)	1.5 (12.5)	-0.3 (14.9)	0.5 (14.5)
Systolic blood pressure Day 197	0.7 (15.8)	0.6 (14.0)	-3.6 (13.5)	-0.4 (13.6)
Systolic blood pressure Day 225	2.8 (14.3)	1.7 (14.8)	-0.6 (15.1)	-0.3 (14.7)
Systolic blood pressure Day 253	-1.8 (15.5)	0.7 (14.4)	-0.9 (15.6)	0.2 (14.5)
Systolic blood pressure Day 325/405	-1.8 (12.8)	0.7 (14.1)	-2.5 (14.7)	0.1 (16.0)
Diastolic blood pressure Day 10	-0.2 (6.0)	0.6 (8.5)	-0.3 (8.4)	-0.4 (8.7)
Diastolic blood pressure Day 29	0.3 (8.5)	-1.3 (8.7)	-1.1 (9.7)	-1.3 (9.1)
Diastolic blood pressure Day 57	-1.1 (8.5)	-0.5 (8.4)	-0.9 (8.9)	-0.4 (8.5)
Diastolic blood pressure Day 85	-0.1 (9.0)	-0.5 (10.5)	-0.9 (8.9)	-0.6 (9.2)
Diastolic blood pressure Day 113	-0.3 (8.5)	0.1 (9.4)	-0.5 (8.9)	1.0 (9.1)
Diastolic blood pressure Day 122	-3.7 (10.4)	-3.9 (8.0)	-2.0 (7.5)	4.1 (12.3)
Diastolic blood pressure Day 141	-1.5 (8.4)	-1.1 (9.6)	-0.3 (8.5)	0.2 (7.9)
Diastolic blood pressure Day 169	-0.4 (9.5)	-0.3 (9.2)	-0.8 (9.0)	-0.4 (9.2)
Diastolic blood pressure Day 197	-1.6 (7.7)	0.0 (9.5)	-2.0 (9.8)	-0.3 (9.0)
Diastolic blood pressure Day 225	0.4 (9.5)	-1.6 (9.8)	-0.9 (8.8)	-0.8 (8.4)
Diastolic blood pressure Day 253	-3.7 (7.9)	-0.1 (10.7)	-1.0 (9.9)	-0.4 (9.3)
Diastolic blood pressure Day 325/405	-1.8 (8.5)	-0.5 (9.1)	-1.5 (10.3)	-0.7 (9.8)

No statistical analysis provided for Vital signs (change in systolic and diastolic blood pressure from baseline) over time

15. Secondary Outcome Measure: Vital signs (change in Heart rate from baseline) variables over time [ Time Frame: From baseline to Day 325/405. Day 325/405: for participants who completed the study under CSP Amendment 1 & 2, the end of study visits were Day 405 and Day 325 respectively. ]

Measure Type	Secondary
Measure Name	Vital signs (change in Heart rate from baseline) variables over time
Measure Description	To assess the safety and tolerability of MEDI6570 compared with placebo
Time Frame	From baseline to Day 325/405. Day 325/405: for participants who completed the study under CSP Amendment 1 & 2, the end of study visits were Day 405 and Day 325 respectively.
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Randomized subjects who received any study treatment will be included in the As-treated Population. Subjects will be analysed according to the actual treatment they received, regardless of their randomized treatment group. Subjects treated within 250 mg group that received at least one 400 mg dose during the study will be analysed according to the 400mg group.

Reporting Groups

	Description
MEDI6570 50 mg	Participants received MEDI6570 50 mg every 4 weeks for 32 weeks
MEDI6570 150 mg	Participants received MEDI6570 150 mg every 4 weeks for 32 weeks
MEDI6570 400 mg	Participants received MEDI6570 400 mg every 4 weeks for 32 weeks
Placebo	Participants received Placebo matched to MEDI6570 every 4 weeks for 32 weeks

Measured Values

	MEDI6570 50 mg	MEDI6570 150 mg	MEDI6570 400 mg	Placebo
Number of Participants Analyzed [units:participants]	39	129	126	126
Vital signs (change in Heart rate from baseline) variables over time [units: beats/min] Mean (Standard Deviation)
Heart rate Day 10	0.4 (9.4)	0.6 (8.0)	0.4 (6.9)	-0.6 (8.6)
Heart rate Day 29	-0.5 (11.4)	0.7 (8.3)	1.3 (8.2)	-1.1 (8.5)
Heart rate Day 57	-2.1 (11.0)	0.9 (8.9)	2.5 (9.7)	1.1 (11.1)
Heart rate Day 85	-3.3 (9.4)	1.0 (9.2)	2.3 (8.3)	1.3 (10.4)
Heart rate Day 113	-1.8 (9.8)	0.5 (10.1)	0.2 (8.7)	0.2 (10.7)
Heart rate Day 122	-3.3 (10.8)	-1.2 (13.4)	-1.3 (7.6)	0.7 (16.0)
Heart rate Day 141	-1.3 (10.4)	0.8 (9.2)	2.0 (9.4)	2.2 (10.4)
Heart rate Day 169	0.7 (10.1)	0.5 (11.0)	3.0 (8.8)	1.5 (9.7)
Heart rate Day 197	2.1 (12.5)	2.3 (9.8)	1.7 (9.5)	1.8 (10.4)
Heart rate Day 225	0.9 (10.0)	1.2 (11.0)	2.5 (10.1)	1.8 (10.4)
Heart rate Day 253	-0.8 (12.2)	0.2 (11.0)	2.1 (10.0)	0.4 (9.4)
Heart rate Day 325/405	0.5 (10.4)	1.3 (9.8)	1.9 (9.4)	0.7 (9.9)

No statistical analysis provided for Vital signs (change in Heart rate from baseline) variables over time

16. Secondary Outcome Measure: Vital signs (change of Weight from baseline to Day 325/405 ) [ Time Frame: From baseline to Day 325/405. Day 325/405: for participants who completed the study under CSP Amendment 1 & 2, the end of study visits were Day 405 and Day 325 respectively ]

Measure Type	Secondary
Measure Name	Vital signs (change of Weight from baseline to Day 325/405 )
Measure Description	To assess the safety and tolerability of MEDI6570 compared with placebo
Time Frame	From baseline to Day 325/405. Day 325/405: for participants who completed the study under CSP Amendment 1 & 2, the end of study visits were Day 405 and Day 325 respectively
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Randomized subjects who received any study treatment will be included in the As-treated Population. Subjects will be analysed according to the actual treatment they received, regardless of their randomized treatment group. Subjects treated within 250 mg group that received at least one 400 mg dose during the study will be analysed according to the 400mg group.

Reporting Groups

	Description
MEDI6570 50 mg	Participants received MEDI6570 50 mg every 4 weeks for 32 weeks
MEDI6570 150 mg	Participants received MEDI6570 150 mg every 4 weeks for 32 weeks
MEDI6570 400 mg	Participants received MEDI6570 400 mg every 4 weeks for 32 weeks
Placebo	Participants received Placebo matched to MEDI6570 every 4 weeks for 32 weeks

Measured Values

	MEDI6570 50 mg	MEDI6570 150 mg	MEDI6570 400 mg	Placebo
Number of Participants Analyzed [units:participants]	39	129	126	126
Vital signs (change of Weight from baseline to Day 325/405 ) [units: kg] Mean (Standard Deviation)	0.316 (4.550)	1.445 (4.863)	1.078 (4.714)	0.786 (5.348)

No statistical analysis provided for Vital signs (change of Weight from baseline to Day 325/405 )

Serious Adverse Events

Time Frame	During study follow-up (from day 1 to day 325/405). Day 325/405: for participants who completed the study under CSP Amendment 1 & 2, the end of study visits were Day 405 and Day 325, respectively.
Additional Description	Subjects initially randomized to the 250 mg group switched dose to 400 mg following CSP amendment 1 and were analysed according to the 400 mg group.

Reporting Groups

	Description
MEDI6570 50 mg	Participants received MEDI6570 50 mg every 4 weeks for 32 weeks
MEDI6570 150 mg	Participants received MEDI6570 150 mg every 4 weeks for 32 weeks
MEDI6570 400 mg	Participants received MEDI6570 400 mg every 4 weeks for 32 weeks
Placebo	Participants received Placebo matched to MEDI6570 every 4 weeks for 32 weeks

Serious Adverse Events

MEDI6570 50 mg

MEDI6570 150 mg

MEDI6570 400 mg

Placebo

Total, serious adverse events

# participants affected / at risk

4/39 (10.26%)

17/129 (13.18%)

10/126 (7.94%)

13/126 (10.32%)

Cardiac disorders

Coronary artery stenosis¹,^†

# participants affected / at risk

0/39 (0.00%)

0/129 (0.00%)

1/126 (0.79%)

0/126 (0.00%)

# events

Eye disorders

Retinal detachment¹,^†

# participants affected / at risk

0/39 (0.00%)

0/129 (0.00%)

1/126 (0.79%)

0/126 (0.00%)

# events

Gastrointestinal disorders

Abdominal pain upper¹,^†

# participants affected / at risk

0/39 (0.00%)

1/129 (0.78%)

0/126 (0.00%)

# events

Gastrointestinal disorders

Diarrhoea¹,^†

# participants affected / at risk

0/39 (0.00%)

0/129 (0.00%)

0/126 (0.00%)

1/126 (0.79%)

# events

Gastrointestinal disorders

Gastrointestinal polyp haemorrhage¹,^†

# participants affected / at risk

0/39 (0.00%)

0/129 (0.00%)

0/126 (0.00%)

1/126 (0.79%)

# events

Gastrointestinal disorders

Ileal perforation¹,^†

# participants affected / at risk

0/39 (0.00%)

1/129 (0.78%)

0/126 (0.00%)

# events

Gastrointestinal disorders

Incarcerated umbilical hernia¹,^†

# participants affected / at risk

1/39 (2.56%)

0/129 (0.00%)

0/126 (0.00%)

# events

Gastrointestinal disorders

Inguinal hernia¹,^†

# participants affected / at risk

0/39 (0.00%)

0/129 (0.00%)

1/126 (0.79%)

0/126 (0.00%)

# events

Gastrointestinal disorders

Omental necrosis¹,^†

# participants affected / at risk

0/39 (0.00%)

1/129 (0.78%)

0/126 (0.00%)

# events

Cardiac disorders

Acute myocardial infarction¹,^†

# participants affected / at risk

0/39 (0.00%)

2/129 (1.55%)

0/126 (0.00%)

1/126 (0.79%)

# events

Gastrointestinal disorders

Pancreatitis¹,^†

# participants affected / at risk

0/39 (0.00%)

0/129 (0.00%)

0/126 (0.00%)

1/126 (0.79%)

# events

Gastrointestinal disorders

Rectal haemorrhage¹,^†

# participants affected / at risk

0/39 (0.00%)

0/129 (0.00%)

1/126 (0.79%)

0/126 (0.00%)

# events

Gastrointestinal disorders

Vomiting¹,^†

# participants affected / at risk

0/39 (0.00%)

0/129 (0.00%)

1/126 (0.79%)

0/126 (0.00%)

# events

General disorders and administration site conditions

Non-cardiac chest pain¹,^†

# participants affected / at risk

1/39 (2.56%)

0/129 (0.00%)

0/126 (0.00%)

# events

Hepatobiliary disorders

Bile duct stone¹,^†

# participants affected / at risk

0/39 (0.00%)

0/129 (0.00%)

0/126 (0.00%)

1/126 (0.79%)

# events

Hepatobiliary disorders

Cholecystitis acute¹,^†

# participants affected / at risk

0/39 (0.00%)

0/129 (0.00%)

0/126 (0.00%)

1/126 (0.79%)

# events

Immune system disorders

Anaphylactic reaction¹,^†

# participants affected / at risk

0/39 (0.00%)

1/129 (0.78%)

0/126 (0.00%)

# events

Infections and infestations

Covid-19¹,^†
8 Subjects initially randomized to the 250 mg group switched dose to 400 mg following CSP amendment 1 and were analysed according to the 400 mg group.

# participants affected / at risk

0/39 (0.00%)

0/129 (0.00%)

1/126 (0.79%)

0/126 (0.00%)

# events

Infections and infestations

Gastroenteritis¹,^†

# participants affected / at risk

1/39 (2.56%)

0/129 (0.00%)

0/126 (0.00%)

# events

Cardiac disorders

Angina pectoris¹,^†

# participants affected / at risk

1/39 (2.56%)

2/129 (1.55%)

0/126 (0.00%)

3/126 (2.38%)

# events

Infections and infestations

Peritonitis¹,^†

# participants affected / at risk

0/39 (0.00%)

1/129 (0.78%)

0/126 (0.00%)

# events

Infections and infestations

Urinary tract infection bacterial¹,^†

# participants affected / at risk

0/39 (0.00%)

0/129 (0.00%)

0/126 (0.00%)

1/126 (0.79%)

# events

Infections and infestations

Urosepsis¹,^†

# participants affected / at risk

1/39 (2.56%)

0/129 (0.00%)

0/126 (0.00%)

# events

Metabolism and nutrition disorders

Diabetes mellitus¹,^†

# participants affected / at risk

0/39 (0.00%)

1/129 (0.78%)

0/126 (0.00%)

# events

Musculoskeletal and connective tissue disorders

Arthralgia¹,^†

# participants affected / at risk

0/39 (0.00%)

0/129 (0.00%)

1/126 (0.79%)

0/126 (0.00%)

# events

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Lung adenocarcinoma¹,^†

# participants affected / at risk

0/39 (0.00%)

0/129 (0.00%)

0/126 (0.00%)

1/126 (0.79%)

# events

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Neuroendocrine tumour¹,^†

# participants affected / at risk

0/39 (0.00%)

1/129 (0.78%)

0/126 (0.00%)

# events

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Prostate cancer¹,^†

# participants affected / at risk

0/39 (0.00%)

0/129 (0.00%)

0/126 (0.00%)

1/126 (0.79%)

# events

Cardiac disorders

Angina unstable¹,^†

# participants affected / at risk

0/39 (0.00%)

3/129 (2.33%)

2/126 (1.59%)

1/126 (0.79%)

# events

Nervous system disorders

Sciatica¹,^†

# participants affected / at risk

0/39 (0.00%)

0/129 (0.00%)

0/126 (0.00%)

1/126 (0.79%)

# events

Nervous system disorders

Transient ischaemic attack¹,^†

# participants affected / at risk

0/39 (0.00%)

1/129 (0.78%)

0/126 (0.00%)

# events

Renal and urinary disorders

Stag horn calculus¹,^†

# participants affected / at risk

0/39 (0.00%)

0/129 (0.00%)

0/126 (0.00%)

1/126 (0.79%)

# events

Respiratory, thoracic and mediastinal disorders

Epistaxis¹,^†
8 Subjects initially randomized to the 250 mg group switched dose to 400 mg following CSP amendment 1 and were analysed according to the 400 mg group.

# participants affected / at risk

0/39 (0.00%)

1/129 (0.78%)

0/126 (0.00%)

# events

Respiratory, thoracic and mediastinal disorders

Haemoptysis¹,^†

# participants affected / at risk

0/39 (0.00%)

0/129 (0.00%)

0/126 (0.00%)

1/126 (0.79%)

# events

Skin and subcutaneous tissue disorders

Psoriasis¹,^†

# participants affected / at risk

0/39 (0.00%)

1/129 (0.78%)

0/126 (0.00%)

# events

Vascular disorders

Aortic aneurysm¹,^†

# participants affected / at risk

0/39 (0.00%)

0/129 (0.00%)

0/126 (0.00%)

1/126 (0.79%)

# events

Cardiac disorders

Atrial fibrillation¹,^†

# participants affected / at risk

0/39 (0.00%)

0/129 (0.00%)

1/126 (0.79%)

0/126 (0.00%)

# events

Vascular disorders

Peripheral artery occlusion¹,^†

# participants affected / at risk

0/39 (0.00%)

0/129 (0.00%)

0/126 (0.00%)

1/126 (0.79%)

# events

Vascular disorders

Peripheral ischaemia¹,^†

# participants affected / at risk

0/39 (0.00%)

0/129 (0.00%)

0/126 (0.00%)

1/126 (0.79%)

# events

Cardiac disorders

Cardiac arrest¹,^†

# participants affected / at risk

0/39 (0.00%)

1/129 (0.78%)

0/126 (0.00%)

# events

Cardiac disorders

Cardiac failure¹,^†

# participants affected / at risk

0/39 (0.00%)

1/129 (0.78%)

0/126 (0.00%)

# events

Cardiac disorders

Cardiogenic shock¹,^†

# participants affected / at risk

0/39 (0.00%)

0/129 (0.00%)

1/126 (0.79%)

0/126 (0.00%)

# events

Cardiac disorders

Coronary artery disease¹,^†

# participants affected / at risk

0/39 (0.00%)

0/129 (0.00%)

0/126 (0.00%)

1/126 (0.79%)

# events

†	Events were collected by systematic assessment
1	Term from vocabulary, MedDRA 26.0

Other Adverse Events

Time Frame	During study follow-up (from day 1 to day 325/405). Day 325/405: for participants who completed the study under CSP Amendment 1 & 2, the end of study visits were Day 405 and Day 325, respectively.
Additional Description	Subjects initially randomized to the 250 mg group switched dose to 400 mg following CSP amendment 1 and were analysed according to the 400 mg group.

Frequency Threshold

Threshold above which other adverse events are reported	5%

Reporting Groups

	Description
MEDI6570 50 mg	Participants received MEDI6570 50 mg every 4 weeks for 32 weeks
MEDI6570 150 mg	Participants received MEDI6570 150 mg every 4 weeks for 32 weeks
MEDI6570 400 mg	Participants received MEDI6570 400 mg every 4 weeks for 32 weeks
Placebo	Participants received Placebo matched to MEDI6570 every 4 weeks for 32 weeks

Other Adverse Events

MEDI6570 50 mg

MEDI6570 150 mg

MEDI6570 400 mg

Placebo

Total, other (not including serious) adverse events

# participants affected / at risk

15/39 (38.46%)

33/129 (25.58%)

37/126 (29.37%)

23/126 (18.25%)

Gastrointestinal disorders

Diarrhoea¹,^†

# participants affected / at risk

2/39 (5.13%)

5/129 (3.88%)

2/126 (1.59%)

3/126 (2.38%)

# events

Gastrointestinal disorders

Nausea¹,^†

# participants affected / at risk

2/39 (5.13%)

1/129 (0.78%)

1/126 (0.79%)

# events

General disorders and administration site conditions

Non-cardiac chest pain¹,^†

# participants affected / at risk

2/39 (5.13%)

5/129 (3.88%)

6/126 (4.76%)

4/126 (3.17%)

# events

General disorders and administration site conditions

Pyrexia¹,^†

# participants affected / at risk

2/39 (5.13%)

1/129 (0.78%)

3/126 (2.38%)

1/126 (0.79%)

# events

Infections and infestations

Covid-19¹,^†
8 Subjects initially randomized to the 250 mg group switched dose to 400 mg following CSP amendment 1 and were analysed according to the 400 mg group.

# participants affected / at risk

2/39 (5.13%)

8/129 (6.20%)

16/126 (12.70%)

6/126 (4.76%)

# events

Cardiac disorders

Angina pectoris¹,^†

# participants affected / at risk

1/39 (2.56%)

7/129 (5.43%)

3/126 (2.38%)

4/126 (3.17%)

# events

Infections and infestations

Influenza¹,^†

# participants affected / at risk

2/39 (5.13%)

4/129 (3.10%)

2/126 (1.59%)

1/126 (0.79%)

# events

Musculoskeletal and connective tissue disorders

Pain in extremity¹,^†

# participants affected / at risk

2/39 (5.13%)

1/129 (0.78%)

1/126 (0.79%)

# events

Respiratory, thoracic and mediastinal disorders

Dyspnoea¹,^†

# participants affected / at risk

2/39 (5.13%)

3/129 (2.33%)

4/126 (3.17%)

3/126 (2.38%)

# events

Respiratory, thoracic and mediastinal disorders

Epistaxis¹,^†

# participants affected / at risk

2/39 (5.13%)

1/129 (0.78%)

2/126 (1.59%)

1/126 (0.79%)

# events

Vascular disorders

Hypertension¹,^†

# participants affected / at risk

2/39 (5.13%)

4/129 (3.10%)

9/126 (7.14%)

# events

Vascular disorders

Hypotension¹,^†

# participants affected / at risk

2/39 (5.13%)

1/129 (0.78%)

4/126 (3.17%)

1/126 (0.79%)

# events

†	Events were collected by systematic assessment
1	Term from vocabulary, MedDRA 26.0

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The agreement is:

	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days . The sponsor cannot require changes to the communication and cannot extend the embargo.
	Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. Restriction Description: The investigator agrees to submit all manuscripts or abstracts to the sponsor for review before submission.

Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
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Results Point of Contact

Name/Title:	Global Clinical Lead
Organization:	AstraZeneca
Phone	1-877-240-9479
E-mail:	[email protected]

Documents available

redacted CSP
Download
redacted SAP
Download
redacted CSR
Download
Trial Results Summaries
Available here

Contacts

Contact

AstraZeneca Clinical Study Information Center

1-877-240-9479

information.center@astrazeneca.com

Sponsors

Collaborators

Inclusion Criteria

Exclusion Criteria

Research Site

Research Site

Research Site

Research Site

Research Site

Research Site

Research Site

Research Site

redacted CSP

redacted SAP

redacted CSR

Trial Results Summaries